Biodegradable block copolymeric compositions for drug delivery

ABSTRACT

An improved drug delivery composition and method of use is disclosed. The composition comprises one or more biodegradable block copolymer drug carriers; and a reconstitution enhancing and enabling agent comprising polyethylene glycol (PEG), a PEG derivative or a mixture of PEG and a PEG derivative. The composition can be administered as is or after being be dissolved or rapidly reconstituted in an aqueous vehicle to afford a homogeneous solution or uniform colloidal systems.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/186,462 filed Jun. 28, 2002, which is a continuation-in-part of U.S.patent application Ser. No. 10/167,768 filed Jun. 11, 2002, the contentsof each are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a composition for drug delivery. Morespecifically, the present invention relates to a copolymeric compositioncomprising a liquid polyethylene glycol (PEG), a PEG derivative or amixture of PEG and PEG derivative; and a biodegradable block copolymericdrug carrier. Particularly, this invention relates to compositionscomprising a to polyethylene glycol (PEG), PEG derivatives, or a mixtureof a PEG and a PEG derivative, and biodegradable ABA, BAB and AB typeblock copolymers that are based on biodegradable hydrophobic polyesteror poly(ortho ester) A blocks and hydrophilic polyethylene glycol (PEG)B blocks.

BACKGROUND OF THE INVENTION

Biodegradable polymers have been used as surgical sutures, wounddressings, and as drug delivery systems. Among them, polylactide (PLA),polyglycolide (PGA) and their copolymers (PLGA) have attracted the mostattention. One example of a biodegradable polymeric drug delivery systemis a system wherein a drug is contained in a biodegradable polymermatrix that is surgically implanted, which is a big disadvantage. In theform of injectable drug delivery systems, polymeric microspheres andnanospheres are known in the art. Commercially available drug deliveryformulations based on PLGA microspheres include Lupron Depot® andNutropin Depot®. Microsphere and nanosphere systems have disadvantagesin that they require special and complex preparation methods.Unfortunately, manufacturing microsphere and nanosphere dosage formsrequires use of toxic or dangerous solvents (e.g., methylene chloride,ethyl acetate) and elaborate procedures (e.g., double emulsions, orcryogenic spraying techniques). The batch size is usually small and thecost is high. In addition, since PLGA biodegradable polymers used canonly be dissolved in organic solvents their preparation requires the useof such solvents which are foreign and harmful to the human body, andcannot be completely removed during manufacture by any known method.Furthermore, some drugs such as peptides and proteins may lose theirpharmacological activity after contact with organic solvents.

An improvement to the aforementioned drug delivery systems is an in situformed depot based on PLGA as disclosed in U.S. Pat. No. 5,599,552. Inthat system, PLGA is dissolved in water-soluble organic solvent(s), suchas N-methyl-2-pyrrolidone, and the drug is either suspended or dissolvedin this polymeric solution. The solution can be injected subcutaneouslyto form an in situ depot to trap the drug in the polymer thatprecipitates as the organic solvent diffuses away. However, the drawbackis the requirement for an organic solvent that is used to dissolve thebiodegradable PLGA polymer. Organic solvents, such asN-methyl-2-pyrrolidone, are foreign to the human body and can causeunwanted side effects both acutely and chronically.

U.S. Pat. No. 5,543,158 discloses nanoparticles or microparticles formedfrom a water-insoluble block copolymer consisting essentially ofpoly(alkylene glycol) and poly(lactic acid). The molecular weight of theblock copolymer is high and the copolymer is insoluble in water. In thenanoparticle or microparticle, the biodegradable moieties of thecopolymer are in the core of the nanoparticle or microparticle and thepoly(alkylene glycol) moieties are on the surface of the nanoparticle ormicroparticle in an amount effective enough to decrease uptake of thenanoparticle or microparticle by the reticuloendothelial system.Nanoparticles are prepared by dissolving the block copolymer and drug inan organic solvent, forming an o/w emulsion by sonication or stirring,and collecting the nanoparticles containing the drug followingprecipitation.

Currently there are few synthetic or natural polymeric materials thatcan be used for the controlled delivery of drugs, including peptide andprotein drugs, because of strict regulatory compliance requirements suchas biocompatibility, low toxicity, having a clearly defined degradationpathway, and safety of the polymers and degradation products. The mostwidely investigated and advanced biodegradable polymers in regard toavailable toxicological and clinical data are the aliphaticpoly(α-hydroxy acids), such as poly(D-, L-, or D, L-lactic acid) (PLA),poly(glycolic acid) (PGA) and their copolymers (PLGA). These polymersare commercially available and are presently used as bioresorbablesutures and in biodegradable microsphere drug delivery systems.FDA-approved microsphere systems for controlled release of leuprolideacetate (Lupron Depot™) and human growth hormone (Nutropin Depot™) arebased on PLGA copolymers. Based on this history of use, PLGA copolymershave been the materials of choice in the initial design of parenteralcontrolled release drug delivery systems using a biodegradable carrier.

Even though there has been some limited success, biodegradable blockcopolymers that are based on biodegradable polyester or poly(orthoester) and polyethylene glycol (PEG) blocks, when used as drug carriers,present problems that are associated with their physicochemicalproperties and attendant methods of fabrication. For example,biodegradable block copolymers are, by design, not stable in aqueousenvironments although shelf-lives of several years can be achieved whenthey are stored frozen. However, elimination of cold storagerequirements would be advantageous in most instances. It is alsodesirable to gain further advantages related to rapid dissolution ofneat block copolymers into aqueous vehicles at normal or ambient roomtemperature conditions. Rapid dissolution of the block copolymerspermits reconstitution at time-of-use to occur, which in turn permitsroom temperature storage of neat block copolymers. Known water solubleblock copolymers are slow to dissolve in water, often requiring severalhours for complete dissolution to occur. Compositions that showaccelerated dissolution kinetics are desired.

Some drugs, such as proteins, are stable in aqueous solutions for onlyshort periods. To compensate for this short-term stability, these drugsare commonly formulated as dry cakes and powders that can be storedunder water-free conditions for much longer periods. Immediately priorto administration the dry cake or powder is reconstituted with anaqueous vehicle. Thus the situation is frequently encountered where itis desirable to have both the drug and the block copolymer drug deliverysystem formulated in reconstitutable forms. To be facile, it is criticalthat reconstitution, i.e., dissolution of the block copolymers and drugbe completed in a short period.

U.S. Pat. No. 5,384,333 discloses an injectable drug deliverycomposition in which a pharmacologically active substance is containedin a copolymer comprising a hydrophilic part and a hydrophobic part.However, the composition has to be heated to a relatively hightemperature such as 38° C. to 52° C., immediately before use and it isdifficult to uniformly distribute the drug in the polymeric composition.U.S. Pat. No. 5,612,052 discloses a block copolymer composition thatwhen contacted with water forms a hydrogel. However, the drugincorporated in this composition is rapidly released. U.S. Pat. No.5,599,552 discloses a composition wherein a water-insolublebiodegradable thermoplastic polymer is dissolved in a water-miscibleorganic solvent, and the resulting composition can be implanted where itthen undergoes a phase transition when in contact with water or bodyfluids. However, the drawback is that it is difficult to use because amono-molecular organic solvent is used to dissolve the biodegradablethermoplastic polymer. Most mono-organic solvents, such asN-methyl-2-pyrrolidone, ethyl lactate, dimethylsulfoxide, etc., causeside effects such as cell dehydration and tissue necrosis, etc. and theymay also cause severe pain at the application sites.

U.S. Pat. No. 5,607,686 discloses a liquid polymeric compositionprepared by mixing a hydrophilic liquid polymer, instead of amono-molecular organic solvent, with a water-insoluble hydrophobicpolymer. When contacted with water the composition undergoes a phasetransition and forms an implant and thus it does not cause a the rapidvolume reduction and it has no special side effects due to the goodcyto-compatibility of the low molecular weight polyethylene oxide.However, the water-insoluble hydrophobic polymers used are notbiodegradable. In addition, the preparation of the composition requiresheating to about 80° C. in order to achieve uniform mixing of thewater-insoluble hydrophobic polymer and the hydrophilic liquid polymer.Therefore, this system may be suitable to use for adherence preventionand wound protection without any physiologically active substance, butit is not suitable for delivery of physiologically active substances,particularly peptide or protein medicines because peptide and proteinmedicines lose their activities at high temperatures. Furthermore,protein medicines are water soluble, thus it is very difficult touniformly incorporate them into the composition. In addition, it is notdisclosed in this patent how the drugs or physiologically activesubstances can be uniformly incorporated in the polymeric composition.Particularly, although polylactide, polyglycolide and their copolymerscan be mixed with polyethylene glycol at high temperatures of 80° C. inorder to obtain a uniform composition, the composition undergoes phaseseparation when it stands for a long period of time due the loweredaffinity of the polylactide, the polyglycolide or their copolymers withpolyethylene glycol. Therefore, it is very difficult to maintain auniform composition.

Sterilization steps are necessary in the preparation of implantformulations. Existing sterilization methods are unsuitable forsustained drug delivery formulations due to properties of the implantcompositions or because the methods are uneconomical or too complicated.For example, it is almost impossible to prepare a uniform solution bymixing a drug, a water-insoluble biodegradable polymer and a hydrophilicpolymer. Therefore, the composition cannot be sterilized by simplemethods such as membrane filtration. Furthermore, although theformulation may be prepared under sterilize conditions, such methods arevery expensive to the extent that the practicability of the preparationmay be lowered.

Therefore, there is a need for a biodegradable drug delivery compositionthat is a flowable liquid or can be rapidly reconstituted in an aqueousvehicle to afford a homogeneous true solution or uniform colloidalsystem in order to be easily prepared and administered to provideimproved drug delivery. Accordingly, the present invention representsimproved drug delivery compositions that minimize or are free of theproblems mentioned above.

SUMMARY OF THE INVENTION

The present invention provides biodegradable compositions for drugdelivery and is a flowable liquid or can be rapidly reconstituted in anaqueous vehicle to afford a homogeneous solution or uniform colloidalsystem, and methods of use thereof for preparing a pharmaceuticallyeffective formulation for delivery of drugs.

The present invention also provides a method for preparing thebiodegradable drug delivery composition and a method for effectivelyadministering such a composition to warm blooded animals. The drugdelivery composition of the present invention can be administereddirectly to a warm blooded animal without an aqueous vehicle, or can beadministered after being rapidly reconstituted in an aqueous vehicle toafford a homogeneous solution or uniform colloidal system. Theadministration can be done by any functional means such as parenteral,ocular, inhalation, transdermal, vaginal, buccal, transmucosal,transurethral, rectal, nasal, oral, peroral, pulmonary, topical or auraland any other means of administration that may be compatible with thepresent invention.

The composition of the present invention comprises: 1) one or morebiodegradable block copolymer drug carriers comprising A-B, A-B-A orB-A-B block, wherein the A block is a biodegradable polyester orpoly(ortho ester) and the B block is polyethylene glycol (PEG) and theweight percentage of the A block is between 20% to 99%; and 2) apolyethylene glycol (PEG), a PEG derivative, or a mixtures of PEG and aPEG derivative, wherein the biodegradable drug carrier is soluble in theliquid PEG and/or PEG derivatives. The weight averaged molecular weightof the biodegradable block copolymer of the present invention ispreferably within the range of 1,000 to 100,000 Daltons, more preferablywithin the range of 1,000 to 50,000 Daltons and most preferably withinthe range of 1,000 to 15,000 Daltons. Preferably, the weight percentageof the hydrophobic A block in the biodegradable block copolymer isbetween 20% to 99%, more preferably 20-85%.

One embodiment of the present invention is a composition comprises: 1)one or more biodegradable block copolymer drug carriers comprising A-B,A-B-A or B-A-B block copolymers, wherein the A block is a biodegradablepolyester or poly(ortho ester) and the B block is polyethylene glycol(PEG), and 2) a polyethylene glycol (PEG), a PEG derivative, or amixtures of PEG and a PEG derivative, wherein at least one of thebiodegradable block copolymers is soluble in an aqueous solution andmiscible with the PEG and/or PEG derivatives. Preferably, thebiodegradable block copolymer drug carriers have a total molecularweight of 2000 to 8000 Daltons, and the weight percentage of the A blockis between 50.1% to 83%. The polyethylene glycol (PEG), a PEGderivative, or a mixtures of PEG and a PEG derivative, preferably have amolecular weight of 150 to 1100 Daltons. The composition can beadministered as is or after being be dissolved or rapidly reconstitutedin an aqueous vehicle to afford a homogeneous solution or uniformcolloidal system. After the administration, the water solublebiodegradable block copolymer may or may not form a gel, depending onmolecular weight and hydrophobic block weight percentage of the blockcopolymer contained in the composition.

Another embodiment of the present invention is a liquid compositioncomprising 1) one or more biodegradable block copolymer drug carrierscomprising A-B, A-B-A or B-A-B block copolymers, wherein the A block isa biodegradable polyester or poly(ortho ester) and the B block ispolyethylene glycol (PEG), and 2) a liquid polyethylene glycol (PEG), aPEG derivative, or a mixtures of PEG and a PEG derivative; wherein thebiodegradable block copolymer is insoluble in an aqueous solution butsoluble in the PEG and/or PEG derivatives. Preferably, the waterinsoluble biodegradable block copolymer drug carriers have a totalmolecular weight of 1000 to 10,000 Daltons, and the weight percentage ofthe A block is between 20% to 99%. The liquid polyethylene glycol (PEG),a PEG derivative, or a mixtures of PEG and a PEG derivative, preferablyhave a molecular weight of 150 to 1100 Daltons. The liquid compositionis a homogeneous solution or uniform colloidal system and can beadministered directly to a warm blooded animal. After theadministration, the liquid composition forms a drug containing depot andslowly releases the active substance over a prolonged period of time andis then decomposed into materials harmless to the human body andexcreted.

Examples of suitable biodegradable water soluble drug carriers includesbiodegradable ABA- or BAB-type triblock copolymers, or AB-type diblockcopolymers based on biodegradable polyester or poly(ortho ester)A-blocks and hydrophilic B polymer block(s) consisting of polyethyleneglycol (PEG). The biodegradable polyester are synthesized from monomersselected from the group consisting of D,L-lactide, D-lactide, L-lactide,D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid,s-caprolactone, 1,4-dioxan-2-one, s-hydroxy hexanoic acid,γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, δ-hydroxyvaleric acid, hydroxybutyric acids, malic acid, and copolymers thereof.

Polyethylene glycol (PEG) is also sometimes referred to as poly(ethyleneoxide) (PEO) or poly(oxyethylene) when incorporated into a blockcopolymer, and the terms can be used interchangeably for the purposes ofthis invention.

In the case where the A-block(s) are PLA/PLGA polyester, the lactatecontent is between about 20 to 100 mole percent, preferably betweenabout 50 to 100 mole percent. The glycolate content is between about 0and 80 mole percent, preferably between about 0 to 50 mole percent. Or,stated differently, when the A-block is PLGA the glycolate content isbetween about 1 and 80 mole percent and preferably between about 1 and50 mole percent and the lactate content is between 20 and 99 molepercent and preferably between 50 and 99 mole percent.

The PEG derivative suitable in the present invention refers to an esteror ortho ester derivatized PEG having a molecular weight of 150 to 1100.Preferably, the ester derivatized PEG is a PEG derivatized from a memberselected from the group consisting of D,L-lactide, D-lactide, L-lactide,D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid,ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid,γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, 6-hydroxyvaleric acid, hydroxybutyric acids, malic acid, and mixtures thereof.The PEG derivative can also be a member represented byR¹—CO—O—(CH₂—CH₂—O)_(n)—CO—R² or R¹—O—(CH₂—CH₂—O)_(n)—R² wherein R¹ andR² are independently members selected from the group consisting of H andC₁ to C₁₀ alkyl and n is an integer between 3 and 20.

The biodegradable block copolymer drug carriers suitable for the presentinvention can form homogeneous, free-flowing solutions or uniformcolloidal systems in an aqueous vehicle or in the liquid PEG or PEGderivatives or mixtures thereof. Homogeneous solutions and uniformcolloidal systems of the drug delivery compositions includes all flowingforms of the compositions of the present invention, with or withoutwater, drug(s), and any additives or excipients as necessary to prepareformulations that are pharmaceutically and therapeutically useful. Thedrug may be present as either a true solution or in a colloidal statesuch as emulsion or a suspension. All forms can act to facilitateadministration of the drug and enhance the therapeutic effect. Suchtherapeutic effects may be optimized by controlling the copolymermolecular weights, compositions, and the relative ratios of thehydrophilic and hydrophobic blocks, ratios of drug to copolymer, ratiosof copolymer to PEG and/or PEG derivatives, and both drug and copolymerconcentrations in the final administered dosage form. Additionaladvantages of this invention will become apparent from the followingdetailed description of the various embodiments.

DETAILED DESCRIPTION OF THE INVENTION

This invention is not limited to the particular configurations, processsteps, and materials disclosed herein, as such configurations, processsteps, and materials may vary somewhat. It is also to be understood thatthe terminology employed herein is used for the purpose of describingparticular embodiments only, and is not intended to be limiting sincethe scope of the present invention will be limited only by the appendedclaims and equivalents thereof.

In this specification and the appended claims, the singular forms “a,”“an,” and “the” include plural references unless the context clearlydictates otherwise. Thus, for example, reference to a composition fordelivering “a drug” includes reference to one, two, or more drugs. Indescribing and claiming the present invention, the following terminologywill be used in accordance with the definitions set out below.

“Effective amount” means an amount of a drug, biologically active agentor pharmacologically active agent that provides the desired local orsystemic effect.

“Copolymer solution”, when used in reference to a biodegradable blockcopolymer contained in such a solution, shall mean an aqueouscomposition having such biodegradable block copolymer drug carriereither dissolved to form a homogeneous solution or uniform colloidalsystem.

“Drug formulations”, “drug delivery compositions”, and the like, shallmean the combination of drug, the block copolymer drug carrier, and PEG,PEG derivatives, or mixtures of PEG and PEG derivatives. They shallinclude all combinations of the drug with the block copolymer and PEG,PEG derivatives, or mixtures thereof.

“Aqueous solution”, “aqueous vehicle” and the like, shall include waterwithout additives or aqueous solutions containing additives orexcipients such as pH buffers, components for tonicity adjustment,antioxidants, preservatives, drug stabilizers, etc., as commonly used inthe preparation of pharmaceutical formulations.

“Drug solution”, “solubilized drug”, “dissolved drug” and all otherterms that refer to the drug in a solution or dissolved state includesthe drug being present as either a homogeneous solution, micellarsolution, or in a colloidal state such as emulsion or a suspension.Thus, solubilized drugs and drug solutions include all flowing forms ofthe drug delivery compositions of the present invention. All forms canact to facilitate administration of the drug and enhance the therapeuticto effect.

“Reconstitution” refers to mixing of biodegradable block copolymer drugcarriers and the PEG, PEG derivatives or mixtures thereof with anaqueous solvent system to create a homogenous solution or uniformcolloidal system. This is in addition to the more traditional definitionof reconstitution where drug and excipients are mixed with a solvent,usually aqueous, immediately before administration.

“Enhanced reconstitution properties” refers to properties that enablerapid reconstitution of block copolymeric drug carriers to the finalphysical state as either a true solution or a uniform colloidal system.The reconstitution process occurs within a short period of time,typically between 0.01 minutes to 120 minutes, preferably within 0.01minutes to 60 minutes, and most preferably within 0.01 minutes to 30minutes.

“Reverse thermal gelation” is the phenomenon whereby an aqueous solutionof a block copolymer spontaneously increases in viscosity, and in manyinstances transforms into a semisolid gel, as the temperature of thepolymer solution is increased above the gelation temperature of theblock copolymer solution. For the purpose of the invention, the term gelincludes both the semisolid gel state and the high viscosity state thatexists above the gelation temperature. When cooled below the gelationtemperature the gel spontaneously reverses to reform the lower viscositypolymer solution. This cycling between the solution and the gel may berepeated indefinitely because the sol/gel transition does not involveany change in the chemical composition of the polymer solution. Allinteractions to create the gel are physical in nature and do not involvethe formation or breaking of covalent bonds.

“Administration” is the means by which drug formulations are presentedto humans and other warm-blooded animals in effective amounts, andincludes all routes for dosing or administering drugs, whetherself-administered or administered by medical practitioners.

“Parenteral” shall mean administration by means other than through thedigestive tract such as by intramuscular, intraperitoneal,intra-abdominal, subcutaneous, intrathecal, intrapleural, intravenousand intraarterial means.

“Depot” means a localized site in the body containing concentratedactive agents or drugs. Examples of formulations that form depots aregels, implants, microspheres, matrices, particles, etc.

“Biodegradable” means that the block copolymer or oligomer canchemically break down or degrade within the body to form nontoxiccomponents. The rate of degradation can be the same or different fromthe rate of drug release.

“Drug” shall mean any organic or inorganic compound or substance havingbiological or pharmacological activity that can be adapted or used for atherapeutic purpose.

“Peptide,” “polypeptide,” “oligopeptide” and “protein” shall be usedinterchangeably when referring to peptide or protein drugs and shall notbe limited as to any particular molecular weight, peptide sequence orlength, field of bioactivity or therapeutic use unless specificallystated.

“PLGA” shall mean a copolymer or copolymer radicals derived from thecondensation copolymerization of lactic acid and glycolic acid, or, bythe ring opening copolymerization of lactide and glycolide. The termslactic acid and lactate are used interchangeably; glycolic acid andglycolate are also used interchangeably.

“PLA” shall mean a polymer derived from the condensation of lactic acidor by the ring opening polymerization of lactide.

“PGA” shall mean a polymer derived from the condensation of glycolicacid or by the ring opening polymerization of glycolide.

“Biodegradable polyester or poly(ortho ester)s” refers to anybiodegradable polyester or poly(ortho ester)s. The polyesters arepreferably synthesized from monomers selected from the group consistingof D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid,L-lactic acid, glycolide, glycolic acid, ε-caprolactone,1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxybutyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyricacid, malic acid, and mixtures thereof.

“Ortho ester” is a carbon which single bonded to three oxygen atomscovalently.

The present invention is based on the discovery of PEG, PEG derivativesor mixtures thereof that can, in minutes, efficiently accelerate thedissolution of the biodegradable block copolymer drug carriers into anaqueous medium. The liquid PEG, PEG derivatives or mixtures thereof ofthe present invention can also dissolve the biodegradable blockcopolymer drug carriers to create a flowable drug delivery composition.The “PEG, PEG derivatives or mixtures thereof” of the present inventionhave a weight averaged molecular weight of 150 to 1100. The PEGderivative suitable in the present invention refers to an ester or orthoester derivatized PEG having a molecular weight of 150 to 1100.Preferably, the ester derivatized PEG is a PEG derivatized from a memberselected from the group consisting of D,L-lactide, D-lactide, L-lactide,D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid,ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid,γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, δ-hydroxyvaleric acid, hydroxybutyric acids, malic acid, and mixtures thereof.The PEG derivative can also be a member represented byR¹—CO—O—(CH₂—CH₂—O)_(n)—CO—R² or R¹—O—(CH₂—CH₂—O)_(n)—R² wherein R¹ andR² are independently members selected from the group consisting of H andC₁ to C₁₀ alkyl and n is an integer between 3 and 20.

The biodegradable block copolymer drug carriers of the present inventionmay be soluble in an aqueous solution, in the liquid PEG, PEGderivatives or mixtures thereof, or both. Examples of some of thesebiodegradable block copolymer drug carriers are disclosed in U.S. Pat.No. 6,201,072 and pending U.S. patent application Ser. Nos. 09/559,799;09/971,074, filed on Oct. 3, 2001 and 09/971,082 filed on Oct. 3, 2001,hereby fully incorporated by reference. The composition can beadministered as is or after being dissolved or rapidly reconstituted inan aqueous vehicle to afford a homogeneous solution or uniform colloidalsystem. After the administration, the water soluble biodegradable blockcopolymer may or may not form a gel, depending on molecular weight andhydrophobic block weight percentage of the block copolymer contained inthe composition. Water soluble biodegradable block copolymers areprepared wherein the hydrophilic B-block(s) make up about 17 to 49.9% byweight of the copolymer and the hydrophobic A-block or blocks make upabout 50.1 to 83% by weight of the copolymer. The weight ratio of thewater soluble biodegradable block copolymer drug carrier and the PEG,PEG derivatives, or mixtures of PEG and PEG derivatives, is between 5:1and 1:99. This composition can be administered as is or after beingquickly reconstituted in water or an aqueous solution and form a polymersolution comprising the composition of the present invention in water orthe aqueous solution at a weight ratio between 2:1 and 1:10000.

Alternatively, the biodegradable block copolymer may be insoluble in anaqueous solution but is soluble in the liquid polyethylene glycol, PEGderivatives or mixtures thereof. In this case, the liquid composition isa homogeneous solution or uniform colloidal system and can beadministered directly to a warm blooded animal. After theadministration, the liquid composition forms a drug containing depot andslowly releases the active substance over a prolonged period of time andis then decomposed into materials harmless to the human body andexcreted. In the liquid composition of the present invention, the weightratio of the biodegradable block copolymer to the PEG, PEG derivativesor mixtures thereof is preferably within the range of 5:1 to 1:99, andmore preferably within the range of 2:1 to 1:99 and most preferablywithin the range of 1:2 to 1:5.

In one embodiment, the biodegradable drug carrier comprises ABA-type orBAB-type triblock copolymers, AB-type diblock copolymers or mixturesthereof, where the A-blocks are relatively hydrophobic and comprises abiodegradable polyester or poly(ortho ester), and the B-blocks arerelatively hydrophilic and comprises polyethylene glycol (PEG), saidcopolymer having a hydrophobic content of between 50.1 to 83% by weightand hydrophilic content of between 17 to 49.9% by weight, and an overallblock copolymer molecular weight of between 2000 and 8000. The drugcarriers exhibit water solubility at temperatures below normal mammalianbody temperatures and undergoes reversible thermal gelation to thenexist as a gel at temperatures equal to physiological mammalian bodytemperatures.

In another embodiment, the biodegradable drug carrier is an ABA-type,BAB-type, or AB-type block copolymer, or mixtures thereof, where theA-blocks are relatively hydrophobic and comprises a biodegradablepolyester or poly(ortho ester), and the B-blocks are relativelyhydrophilic and comprises polyethylene glycol (PEG), said blockcopolymer having a hydrophobic content of between 50.1 to 65% by weightand a hydrophilic content of between 35 to 49.9% by weight, and anoverall block copolymer weight-averaged molecular weight of between 2400and 4999. The drug carriers are water soluble and capable of enhancingthe solubility of drugs, hydrophobic drugs in particular, in water, toform a drug solution.

In still another embodiment, the polymeric drug carrier comprisesbiodegradable polyester or poly(ortho ester) oligomers, and particularlyPLA/PLGA oligomers having a weight averaged molecular weight of between400 and 10,000, mixed with biodegradable ABA-type or BAB-type triblockcopolymers, or AB-type diblock copolymers having a weight averagedmolecular weight of between 2400 and 4999. The block copolymers have50.1 to 65% by weight of the hydrophobic A block(s) comprisingbiodegradable polyester or poly(ortho ester)s and 35 to 49.9% by weightof the hydrophilic B block(s) consisting of polyethylene glycol (PEG).

The PEG, PEG derivatives or mixtures thereof used in the presentinvention dissolves or uniformly mixes with the biodegradable blockcopolymer and so reduces the viscosity and increases the fluidity of thecomposition. The compositions of the present invention are flowableliquids or can be easily formulated with an aqueous vehicle to afford afluid homogeneous solution or uniform colloidal system. In the casesthat the block copolymeric drug carrier is insoluble in an aqueousvehicle but soluble in the liquid PEG and/or PEG derivatives, when incontact with water or body fluids, the block copolymer forms a drugdepot. In cases that the block copolymeric drug carrier is soluble in anaqueous vehicle and miscible with the PEG and/or PEG derivatives, thecomposition can be easily administered as is or reconstituted with anaqueous vehicle. After the administration, the block copolymer drugcarrier may or may not form a drug depot. Therefore, the liquid PEG, PEGderivative or mixtures thereof of the present invention should be amaterial that does not cause loss of activity of the physiologicallyactive substance.

For purposes of disclosing molecular weight parameters, all reportedmolecular weight values are based on measurements by ¹H-NMR or GPC (gelpermeation chromatography) analytical techniques. The reported weightaveraged molecular weights and number averaged molecular weights weredetermined by GPC and ¹H-NMR, respectively. The reportedlactide/glycolide ratios were calculated from ¹H-NMR data. GPC analysiswas performed on a Styragel HR-3 column, or equivalent, calibrated withPEG standards using RI detection and chloroform as the eluent, or on acombination of Phenogel, mixed bed, and 500 Å columns calibrated withPEG standards using RI detection and tetrahydrofuran as the eluent forthe ABA and BAB triblock copolymers.

ABA-type and BAB-type triblock copolymers, and AB-type diblockcopolymers may be synthesized by ring opening polymerization, orcondensation polymerization. Additionally, the B-blocks may, in certaininstances, be coupled to the A-blocks by ester or urethane links and thelike. Condensation polymerization and ring opening polymerizationprocedures may be utilized as may the coupling of a monofunctionalhydrophilic B block to either end of a difunctional hydrophobic A blockin the presence of coupling agents such as isocyanates. Furthermore,coupling reactions may follow activation of functional groups withactivating agents, such as carbonyl diimidazole, succinic anhydride,N-hydroxy succinimide, p-nitrophenyl chloroformate and the like.

The hydrophilic B-block is formed from PEG of an appropriate molecularweight. PEG was chosen as the hydrophilic B-block because of its uniquebiocompatibility, nontoxic properties, hydrophilicity, solubilizationproperties, and rapid clearance from a patient's body. The hydrophobicA-blocks are utilized because of their biodegradable, biocompatible, andsolubilization properties. The in vitro and in vivo degradation ofhydrophobic, biodegradable polyester or poly(ortho ester) A-blocks arewell understood and the degradation products are readily metabolizedand/or eliminated from the patient's body.

Drugs that may be incorporated with the drug delivery compositions ofthe present invention can be any bioactive agent, but particularadvantage is achieved with bioactive agents having limited solubility ordispersibility in an aqueous or hydrophilic environment, or anybioactive agent that requires enhanced solubility or dispersibility.Without limiting the scope of the present invention, suitable drugsinclude those drugs presented in current edition of Goodman and Gilman's“The Pharmacological Basis of Therapeutics” or the current edition ofThe Merck Index. Both volumes list drugs suitable for numerous types oftherapeutic applications, including drugs in the followingcategories:drugs acting at synaptic and neuroeffector junctional sites,drugs acting on the central nervous system, drugs that influenceinflammatory responses, drugs that affect the composition of bodyfluids, drugs affecting renal function and electrolyte metabolism,cardiovascular drugs, drugs affecting gastrointestinal function, drugsaffecting uterine motility, chemotherapeutic agents for parasiticinfections, chemotherapeutic agents for microbial diseases,antineoplastic agents, immunosuppressive agents, drugs affecting theblood and blood-forming organs, hormones and hormone antagonists,dermatological agents, heavy metal antagonists, vitamins and nutrients,vaccines, oligonucleotides and gene therapies.

Incorporating one or more drugs mentioned in the above categories withthe compositions of the present invention to form drug deliverycompositions which can be dissolved or easily reconstituted to form anaqueous solution or uniform colloidal system can be achieved by simplyadding the drug to the liquid composition or an aqueous solutions of thecompositions of the present invention, or by mixing the drug with thecompositions of the present invention and thereafter adding water or anaqueous solution to form a solution or uniform colloidal system.

Mixtures of the compositions of the present invention withpeptide/protein drugs, and/or other types of drugs, may be prepared asflowable drug delivery formulations or formulations that may be easilyreconstituted in the form of a solution or dispersion. The flowableformulation is then administered parenterally, topically, transdermally,transmucosally, inhaled, or inserted into a cavity such as by ocular,vaginal, transurethral, rectal, nasal, oral, peroral, buccal, pulmonaryor aural administration to a patient. Many of the solubilized drugformulations prepared by implementing the present invention may bediluted in an i.v. bag or by other means, and administered to a patientfor an extended period, without precipitation of the drug. Due to thebiocompatibility of the materials and the free flowing nature of thesystem at physiological temperatures, this system will cause minimaltoxicity and minimal mechanical irritation to the surrounding tissue.

A distinct advantage to the compositions of this invention lies in theability of PEG, PEG derivatives or mixtures thereof to reduce theviscosity of the biodegradable block copolymer drug carriers into a formthat is flowable liquid or can be quickly reconstitutable in water or anaqueous solution to form a solution or uniform colloidal system for drugdelivery. In one possible configuration, a dosage form comprised of asolution of the block copolymer drug carrier and a PEG, PEG derivativesor mixtures thereof that contains drug is administered to the body. Inanother possible configuration, the drug delivery composition of thepresent invention may be quickly dissolved or reconstituted by usingwater or other aqueous solutions.

The only limitation as to how much drug can be dissolved or dispersed inthe drug delivery composition of the present invention is one offunctionality, namely, the drug:copolymer ratio may be increased untilthe properties of the mixture are adversely affected to an unacceptabledegree, or until to the properties of the system are adversely affectedto such a degree as to make administration of the system unacceptablydifficult. Generally speaking, it is anticipated that in most instanceswhere dissolution is desired, the drug will be present at between about10⁻⁶ to about 100 percent by weight of the combined weight the blockcopolymer drug carrier and the PEG, PEG derivatives or mixtures thereof,with ranges of between about 0.001% to 25% by weight being the mostcommon. For example, having the drug present at 100% by weight of thecombined weight of the block copolymer drug carrier and the PEG, PEGderivatives or mixtures thereof means that the drug and combined weightthe block copolymer drug carrier and the PEG, PEG derivatives ormixtures thereof are present in equal amounts (i.e., equal weights).Generally speaking, it is anticipated that in most instances wheredispersion is desired, the upper drug:copolymer ratio couldsubstantially exceed the range noted above for dissolution. These rangesof drug loading are illustrative and will include most drugs that may beutilized in the present invention. However, such ranges are not limitingto the invention should drug loadings outside this range be functionaland effective.

The present invention thus provides compositions comprisingbiodegradable block copolymer drug carriers and PEG, PEG derivatives ormixtures thereof that are flowable liquids or can be rapidlyreconstituted in an aqueous vehicle to afford useful forms that may beeither homogeneous true solutions or uniform colloidal systems. The drugsolution formed with the drug delivery compositions of the presentinvention has desirable physical stability, therapeutic efficacy, andtoxicology. The PEG, PEG derivatives or mixtures thereof of the presentinvention can be used for water soluble or water insoluble blockcopolymeric drug carriers, particularly for biodegradable di- ortriblock copolymers that have reverse gelation properties and/orpolymers that can enhance the solubility of drugs, especiallyhydrophobic drugs.

The following are examples that illustrate preferred embodiments of theinvention but are intended as being representative only.

Example 1

PEG-300 (107.6 g) was placed in a 250-mL round bottom flask and driedunder vacuum (0.2 torn, 90° C.) for 3 hours. D,L-Lactide (33.4 g) andglycolide (9.0 g) was added and the head-space was replaced by driednitrogen. The mixture was brought to 135° C. and the reaction wasinitiated by adding stannous octoate (20 mg) via a dry syringe. Thereaction mixture was allowed to stir under dry nitrogen at 155° C. forfour additional hours. Residual monomers were removed under vacuum (0.2torr, 90° C., 2 hr). The resulting PEG derivative (D1) was a clearfree-flowing liquid.

Example 2

Following the procedure described in Example 1, the following PEGderivatives were prepared.

TABLE 1 PEG derivatives synthesized by the method described in Example 1PEG weight Glycolide D,L-Lactide ID PEG (gram) (gram) (gram) D2 PEG200NF30.0 7.62 28.38 D3 PEG200NF 33.33 5.64 21.02 D4 PEG300NF 57.14 4.8418.02 D5 PEG600NF 50.0 4.23 15.75 D6 Triethylene 50.0 4.23 15.77 glycolD7 PEG300NF 50.25 19.75 — D8 PEG300NF 86.15 24.67 9.19 D9 PEG300NF 100.5— 39.5

Example 3

PEG-300 (40 g) was placed in a 250-mL round bottom flask. Moisture wasremoved by drying under vacuum (0.2 torr) at 90° C. for 3 hours. Aceticanhydride (30 g) was added and the reaction mixture was brought toreflux under nitrogen over 48 hours. Excess acetic anhydride was removedby vacuum distillation at 100° C. for 24 hours. The resulting PEGderivative (D10) was a clear, free-flowing liquid.

Example 4

This example illustrates the synthesis of the ABA-type triblockcopolymer PLGA-PEG-PLGA by ring opening copolymerization.

PEG 1000 NF (65.3 g) and PEG 1450 NF (261 g) was dried under vacuum (1mmHg) at 130° C. for 5 hours. D, L-Lactide (531.12 g) and glycolide(142.6 g) were added to the flask and heated to 155° C. to afford ahomogenous solution. Polymerization was initiated by the addition of 250mg stannous octoate to the reaction mixture. After maintaining thereaction for five hours at 145° C., the reaction was stopped and theflask was cooled to room temperature. Unreacted lactide and glycolidewere removed by vacuum distillation. The resulting PLGA-PEG-PLGAcopolymer mixture (ABA 1) had a weight averaged molecular weight (Mw) of4255 as measured by GPC. This triblock copolymer mixture is watersoluble at room temperature. A 23% by weight aqueous solution of thistriblock copolymer mixture had a gel temperature between 30° C. and 37°C.

Example 5

Using the procedure described in Example 4, the following copolymers orcopolymer mixtures were synthesized:

TABLE 2 Copolymers synthesized using the procedure described in Example3 LA/GA PEG1/ Block Molar PEG1 PEG2 PEG2 MW Copolymer Ratio MW MW wtRatio (Dalton) Remarks PLG-PEG-PLG 75/25 1000 — 100/0 4250 Water (ABA 2)soluble PLG-PEG-PLG 75/25 1450 — 100/0 3950 Water (ABA 3) solublePLA-PEG-PLA 100/0  1000 1450  10/90 3980 Water (ABA 4) solublePLG-PEG-PLG 75/25 1450 — 100/0 7540 Water (ABA 5) insoluble PLA-PE-PLA100/0  1000 600  80/20 6500 Water (ABA 6) insoluble

Example 6

AB diblock copolymer was synthesized by placing 25.7 g of PEG-Me (Mw:2000) in a 250 mL 3-neck round bottom reaction flask. Water was removedby heating in an oil bath (155° C.) under vacuum (0.5 torr) for 3 hours.The reaction flask was then raised out of the oil bath and the vacuumwas released.

D,L-Lactide (32.0 g) was weighed and added to the reaction flask. Theheadspace was replaced with dry nitrogen by repeated evacuation andflushing with dry nitrogen 5 times.

The flask was then lowered and immersed in a 155° C. oil bath. Once thecontent was melted and the internal temperature reached 150° C., 2 drops(200 ppm) of stannous 2-ethylhexanoate was added to initiate thepolymerization. The reaction mixture was stirred using an overheadstirrer for 8 hours at a rate of 100-200 rpm. The temperature was thenreduced to 140° C., and the residual monomer was removed under reducedpressure (<1 torr) over 1 hour. The residue is a translucent, off-whitesolid having a molecular weight of 5450.

One gram of the diblock copolymer was added to 4 grams of PEG derivative(D10) to afford a clear and free flowing liquid. Upon addition of themixture to 37° C. water, the mixture turned cloudy due to apparentprecipitation of the water insoluble diblock copolymeric component.

Example 7

Me-PEG (MW 550; 48.6 g) was transferred into a 250 mL 3-neck roundbottom reaction flask. The oil bath was heated to 100° C. The moltenPEG-Me was stirred under vacuum for 5 hours to remove water. Thereaction flask was then raised outside of the oil bath and the vacuumwas released. D,L-Lactide (97.68 g) and glycolide (26.47 g) were weighedand added the reaction flask. The headspace was replaced with drynitrogen. The flask was then immersed into a 155° C. oil bath. Once theD,L-lactide was melted and the temperature inside the reaction flaskreached 150° C., 2 drops (200 ppm) of stannous 2-ethylhexanoate wasadded to the reaction flask. The reaction was stirred continuously for 8hours at a rate of 100-150 rpm.

The oil bath temperature was reduced to 140° C. and the reaction flaskwas attached to vacuum (<1 torr) for an hour to remove residual monomer.The diblock copolymer had honey-like consistency with molecular weightof 2010. The residue (145 g) was added to 1,6-diisocynatohexane (6.06 g)via an oven dried syringe and the reaction mixture was allowed to stirat 140° C. for 2 additional hours. The residue was purified bydissolving the polymer in water and precipitation at 70° C. Water wasremoved by lyophilization and the residual BAB triblock copolymer had amolecular weight of 4250.

One gram of the polymer was dissolved in 4 gram of PEG derivative (D 4)and the mixture was added to 25 mL of warm water (37° C.) via a 24-Gneedle. Upon addition of the mixture to 37° C. water, the mixture turnedcloudy due to apparent precipitation of the water insoluble diblockcopolymeric component.

Example 8

The use PEG derivatives for reconstitution are illustrated in thisexample.

The PEG derivative (1.5 g) prepared from Example 1 were added to 1 gramof PLGA-PEG-PLGA triblock copolymer prepared from Example 4. The twocomponents were intimately mixed into a homogeneous mixture. To themixture, water for injection (5 g) was added shaken. The mixture took 1minute to reconstitute. The resulting aqueous solution had a gelationtemperature at 30° C. and 37° C.

Zinc insulin (5 mg) was reconstituted with 5 mL of the aqueous solutionand the solution was injected into 37° C. water. The solution rapidlygelled.

Example 9

Zn-insulin (5 mg) is suspended a mixture composed of a triblockcopolymer (ABA 6; 1 g) dissolved in 6 g of PEG derivative (D 2). Themixture is a free-flowing liquid. One mL of the suspension is injectedinto warm water (25 mL; 37° C.). Upon addition of the mixture to 37° C.water, the mixture turned cloudy due to apparent precipitation of thewater insoluble triblock copolymeric component.

Example 10

The PEG derivatives (D6; 4 g) were added to 1 gram of PLGA-PEG-PLGAtriblock copolymer (ABA3). Also added to the mixture was 50 mg ofpaclitaxel. The mixture was intimately mixed into a homogeneous mixtureat ca. 40° C. for ca. 20 minutes. The mixture was a clear free flowingliquid. One gram of the mixture was added to a beaker containing 25 mLof warm water (37° C.). The mixture apparently dissolved rapidly toafford a clear solution or uniform colloid.

Example 11

The PEG derivative (3 g) from Example 1 were intimately mixed with 1gram of PLGA-PEG-PLGA triblock copolymer (ABA3) and 0.08 g ofpoly(D,L-lactate-co-glycolate) (MW 1200) into a homogeneous mixture.Paclitaxel (75 mg) was dissolved into the mixture with gentle stirringat ca. 45° C. After equilibrated to ambient temperature, water forinjection (5 g) was added and the mixture was shaken. The mixtureapparently dissolved rapidly to afford a clear solution or uniformcolloid.

Example 12

This example illustrate the synthesis of poly(ortho ester) AB diblockcopolymer.

Dried 1,4-cyclohexanedimethanol (2.6 g), PEG 2000 methyl ether (4 g) isheated at 70° C. with DETOSU(3,9-bis(ethylidene)-2,4,8,10-tetraoxaspiro[5,5]undecane; 4.35 g) indried 1,4-dioxane (100 mL) over 8 hour. The solvent is removed undervacuum (0.5 torr; 70° C.) over 40 hours. The resulting poly(ortho ester)AB diblock copolymer is a transparent copolymer.

Example 13

This example illustrates the synthesis of PEG ortho ester derivative.PEG 300 (25.0 g) is heated in a round bottomed flask under vacuum at 90°C. for 3 hours to remove residual water. Molten DETOSU(3,9-bis(ethylidine)-2,4,8,10-tetraoxaspiro[5,5]undecane) (4.0 grams) isadded to the flask through an oven dried syringe. The mixture is allowedto heat at 90° C. over 5 hours. The resulting PEG ortho ester derivativeis a clear liquid.

Example 14

This example illustrates the use of PEG ortho ester derivative.Paclitaxel (50 mg) is dissolved with mild heating into a mixture of PEGderivative (15 g) synthesized in Example 13 and an AB diblock poly(orthoester) copolymer (3 g) prepared in Example 12. The resulting mixture isa clear liquid. Upon addition of the mixture to 37° C. water, themixture turned cloudy due to apparent precipitation of the waterinsoluble diblock copolymeric component.

The above description will enable one skilled in the art to make acomposition comprising biodegradable block copolymer drug carriers andPEG, PEG derivatives, or a mixtures thereof, said composition is aflowable liquid or can be rapidly reconstituted in an aqueous vehicle tohomogeneous solutions or uniform colloidal systems. Although the drugdelivery compositions are described to show the functionality of thecompositions of the present invention, these descriptions are notintended to be an exhaustive statement of all drug carriers that can berendered soluble and/or constitutable by the compositions of the presentinvention. Certainly, numerous other drug carriers or drugs from variouscategories of therapeutic agents are well suited for the drug deliverycompositions described in this invention. It will be immediatelyapparent to one skilled in the art which various modifications may bemade without departing from the scope of the invention that is limitedonly by the following claims and their functional equivalents.

We claim:
 1. A composition comprising: (a) one or more biodegradableblock copolymer drug carriers comprising A-B, A-B-A or B-A-B blockcopolymers having a total weight average molecular weight of 2000 to4990 Daltons, wherein the A block is a biodegradable polyester orpoly(ortho ester) and the B block is polyethylene glycol (PEG), and theweight percentage of the A block is between 51% to 83% and the weightpercentage of the B block is between 17% to 49%; and (b) a polyethyleneglycol (PEG), a PEG derivative, or a mixture of PEG and a PEGderivative, said PEG or PEG derivative having a molecular weight of 150to 1100 Daltons, wherein the PEG derivative is an ester derivatized PEGand wherein the PEG is derivatized with D,L-lactide, D-lactide,L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide,glycolic acid, ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoicacid, γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone,δ-hydroxy valeric acid, hydroxybutyric acids, malic acid, or mixturesthereof; wherein at least one of component (a) is soluble in an aqueoussolution and miscible with component (b), the weight ratio of component(a) to component (b) is within the range of 2:1 to 1:99, the compositioncan be reconstituted in water or an aqueous solution to form ahomogeneous solution or a uniform colloidal system, the composition isfree of toxic or dangerous organic solvents, and the compositionpossesses reverse thermal gelation properties such that it forms a gelwhen reconstituted and administered to a warm blooded mammal.
 2. Thecomposition according to claim 1 wherein the PEG derivative is an orthoester derivatized PEG.
 3. The composition according to claim 1 whereinthe PEG derivative is represented by R¹—CO—O—(CH₂—CH₂—O)_(n)—CO—R² orR¹—O—(CH₂—CH₂—O)_(n)—R², —wherein R¹ and R² are independently H or C₁ toC₁₀ alkyl and n is an integer between 3 and
 20. 4. The compositionaccording to claim 1 further comprising a drug.
 5. The compositionaccording to claim 4, wherein the drug has limited solubility ordispersibility in an aqueous or hydrophilic environment.
 6. Thecomposition according to claim 4, wherein the drug is present at betweenabout 10⁻⁶ to about 100 percent by weight of the combined weight of theblock copolymer and the PEG, PEG derivative or mixtures thereof.
 7. Thecomposition according to claim 6, wherein the drug is present at betweenabout 0.001% to 25% by weight.
 8. The composition of claim 1, whereinsaid composition can be reconstituted in water or an aqueous solution toform a homogeneous solution or a uniform colloidal system within 0.01minutes to 120 minutes.
 9. The composition of claim 1, wherein saidcomposition can be reconstituted in water or an aqueous solution to forma homogeneous solution or a uniform colloidal system within 0.01 minutesto 60 minutes.
 10. The composition of claim 1, wherein said compositioncan be reconstituted in water or an aqueous solution to form ahomogeneous solution or a uniform colloidal system within 0.01 minutesto 30 minutes.
 11. The composition of claim 1, wherein the weight ratioof the biodegradable block copolymeric drug carrier and the PEG, PEGderivative or mixtures thereof is within the range of 1:2 to 1:5. 12.The composition of claim 1, wherein the PEG or PEG derivative comprisesPEG200NF, PEG300NF, or PEG600NF.
 13. The composition of claim 1, whereinthe PEG or PEG derivative comprises PEG200NF or PEG300NF.
 14. An aqueouscomposition comprising the composition of claim 1 reconstituted in anaqueous vehicle, wherein said composition is a homogeneous solution oruniform colloidal system, said composition being free of organicsolvent.
 15. The aqueous composition of claim 14, wherein the aqueousvehicle is water for injection.
 16. A method of administrationcomprising reconstituting the composition of claim 1 by addition ofwater or an aqueous solution to form a homogeneous solution or a uniformcolloidal system within 0.01 minutes to 120 minutes; administering thehomogeneous solution or uniform colloidal system to a warm bloodedmammal, wherein the composition forms a gel when reconstituted andadministered to a warm blooded mammal.
 17. The method of administrationof claim 16, wherein the administering step is through the parenteralroute.
 18. The method of administration of claim 16, wherein theadministering step is by injection.
 19. A composition comprising: (a)one or more biodegradable block copolymer drug carriers comprising A-B,A-B-A or B-A-B block copolymers having a total weight average molecularweight of 2000 to 4990 Daltons, wherein the A block is a biodegradablepolyester or poly(ortho ester) and the B block is polyethylene glycol(PEG), and the weight percentage of the A block is between 51% to 83%and the weight percentage of the B block is between 17% to 49%; and (b)a PEG derivative, or a mixture of PEG and a PEG derivative, said PEG orPEG derivative having a molecular weight of 150 to 1100 Daltons, whereinthe PEG derivative is an ester derivatized PEG and wherein the PEG isderivatized with D,L-lactide, D-lactide, L-lactide, D,L-lactic acid,D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone,1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxybutyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyricacids, malic acid, or mixtures thereof; wherein at least one ofcomponent (a) is soluble in an aqueous solution and miscible withcomponent (b), the weight ratio of component (a) to component (b) iswithin the range of 2:1 to 1:99, the composition can be reconstituted inwater or an aqueous solution to form a homogeneous solution or a uniformcolloidal system, the composition is free of toxic or dangerous organicsolvents, and the composition possesses reverse thermal gelationproperties such that it forms a gel when reconstituted and administeredto a warm blooded mammal.